Sargentodoxa cuneata suppresses lung adenocarcinoma progression by enhancing cytotoxic CD8(+) T activity through the ACY1/ARG2 interaction.

Cytotoxic CD8(+) T lymphocytes play a pivotal role in anti-tumor immunity by eliminating cancer cells. Sargentodoxa cuneata (Sar) has demonstrated anti-cancer potential. This study investigated the therapeutic potential of Sar in lung adenocarcinoma (LUAD) through its modulation of CD8(+) T cell tumoricidal capacity. CD8(+) T cells were isolated and co-cultured with treated HCC2935 and H1975 LUAD cell lines. The influences on LUAD cells were assessed by detecting cell viability and apoptosis. The impacts on CD8(+) T cells were evaluated by measuring cell cytotoxic activity and IFN-γ and TNF-α secretion. The aminoacylase-1 (ACY1)/arginase-2 (ARG2) interaction was predicted by molecular docking and confirmed by GST pull-down and Co-IP assays. Animal xenograft experiments were used to analyze the therapeutic potential of Sar in vivo. ACY1 and ARG2 were upregulated and positively associated with PD-L1 expression in LUAD samples. Mechanistically, ACY1 physically interacted with ARG2 in LUAD cells. ACY1 inhibited apoptosis in LUAD cells and attenuated cytotoxic activity of CD8(+) T lymphocytes via ARG2. Moreover, Sar induced LUAD cell apoptosis and enhanced CD8(+) T cell cytotoxicity by downregulating ACY1 in vitro. Sar attenuated xenograft tumor development through ACY1 downregulation in vivo. Our study establishes that Sar emerges as a promising therapeutic agent in LUAD by enhancing CD8(+) T tumoricidal capacity through targeting the ACY1/ARG2 co-regulatory axis. GRAPHICAL ABSTRACT: Sargentodoxa cuneata (Sar) reduces ACY1 expression to disrupt the ACY1/ARG2 interaction and thus downregulates PD-L1, consequently inducing LUAD cell apoptosis and enhancing CD8(+) T cell cytotoxicity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-025-00849-w.